Intestinal restriction of Salmonella Typhimurium requires caspase-1 and caspase-11 epithelial intrinsic inflammasomes

Intestinal restriction of <i>Salmonella</i> Typhimurium requires caspase-1 and caspase-11 epithelial intrinsic inflammasomes:

by Shauna M. Crowley, Xiao Han, Joannie M. Allaire, Martin Stahl, Isabella Rauch, Leigh A. Knodler, Bruce A. Vallance

We investigated the role of the inflammasome effector caspases-1 and -11 during Salmonella enterica serovar Typhimurium infection of murine intestinal epithelial cells (IECs). Salmonella burdens were significantly greater in the intestines of caspase-1/11 deficient (Casp1/11^−/−), Casp1^−/− and Casp11^−/− mice, as compared to wildtype mice. To determine if this reflected IEC-intrinsic inflammasomes, enteroid monolayers were derived and infected with Salmonella. Casp11^−/− and wildtype monolayers responded similarly, whereas Casp1^−/− and Casp1/11^−/− monolayers carried significantly increased intracellular burdens, concomitant with marked decreases in IEC shedding and death. Pretreatment with IFN-γ to mimic inflammation increased caspase-11 levels and IEC death, and reduced Salmonella burdens in Casp1^−/− monolayers, while high intracellular burdens and limited cell shedding persisted in Casp1/11^−/− monolayers. Thus caspase-1 regulates inflammasome responses in IECs at baseline, while proinflammatory activation of IECs reveals a compensatory role for caspase-11. These results demonstrate the importance of IEC-intrinsic canonical and non-canonical inflammasomes in host defense against Salmonella.